The goal of this mentored career development award is to facilitate the candidate?s transition to independence as a physician-scientist studying molecular mechanisms of neuroinflammation and neurodegeneration. The candidate is a MD/PhD neurologist with a background in neurodegenerative disease research. The award will help the candidate achieve his short-term goal, to gain research experience in the molecular pathogenesis of neuroimmune activation and neurodegeneration in models of Alzheimer disease (AD)-like pathology and facilitate his transition to an investigator with an independent laboratory. The award will also help position the candidate to achieve his long-term goal of becoming a successful and productive physician-scientist and a leader in academic neurology. The environment in which the proposed research will be conducted is outstanding. The candidate?s primary mentor, Dr. David Holtzman, is an internationally respected scientist and neurologist with a proven track record of excellence in training junior faculty. The candidate?s career development plan includes structured co-mentorship from Dr. John Morris, also an internationally respected neurologist and clinician- scientist, who will supervise the candidate?s clinical training and development of clinical research skills. Drs. Holtzman and Morris have a track record of co-mentoring numerous junior faculty to successful independent research careers in neurology. Didactic learning, presentation of work at scientific meetings, and rigorous training in the responsible conduct of research will ensure a balanced development. The proposed research will examine the role of 25-hydroxycholesterol (25-HC) in modulating the neuroimmune response to ApoE-dependent amyloid pathology and tau-mediated neurodegeneration. Multiple lines of evidence suggest that activation of immune mediators is a critical regulator of AD pathology. However, the exact role that microglia play in modulating AD pathogenesis is still difficult to parse, partly due to discrepant effects of microglial function in models of amyloidosis and tauopathy. Microglial response to amyloid and tau deposition is dependent on apolipoprotein E (ApoE) as evidenced by experiments where ApoE expression is genetically deleted. 25-HC is produced exclusively by microglia, is a potent modulator of microglial response, has been implicated in the pathogenesis of autoimmune neurological disease and modulates the production of ApoE. The goal of this project is to test the hypothesis that microglial production of 25-HC modulates ApoE-dependent neuroinflammatory responses and neurodegeneration in mouse models of amyloid and tau deposition. Clarifying the role of 25-HC and ApoE in these processes will provide insights into AD pathobiology and ultimately should point towards novel therapeutic targets that can be leveraged to treat AD and related dementias. This career development award is an ideal mechanism to provide the candidate with valuable research training which will complement his clinical focus in Aging and Dementia and will help develop a skill set for translating basic science discoveries into effective therapies for patients with neurodegenerative diseases.